WO2002072557A1 - Bis(trifluoromethyl)hydantoins as intermediates for pharmaceutically active ingredients - Google Patents
Bis(trifluoromethyl)hydantoins as intermediates for pharmaceutically active ingredients Download PDFInfo
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- WO2002072557A1 WO2002072557A1 PCT/EP2002/001918 EP0201918W WO02072557A1 WO 2002072557 A1 WO2002072557 A1 WO 2002072557A1 EP 0201918 W EP0201918 W EP 0201918W WO 02072557 A1 WO02072557 A1 WO 02072557A1
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- Prior art keywords
- carboxylic acid
- formula
- groups
- residue
- compound
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- 239000000543 intermediate Substances 0.000 title abstract description 14
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- 239000000725 suspension Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- RFUWRXIYTQGFGA-QRPNPIFTSA-N tert-butyl (2s)-2-amino-4-methylpentanoate;hydron;chloride Chemical compound Cl.CC(C)C[C@H](N)C(=O)OC(C)(C)C RFUWRXIYTQGFGA-QRPNPIFTSA-N 0.000 description 1
- UMELXMIXLCWABX-VIFPVBQESA-N tert-butyl (2s)-3-cyclopropyl-2-formamidopropanoate Chemical compound CC(C)(C)OC(=O)[C@@H](NC=O)CC1CC1 UMELXMIXLCWABX-VIFPVBQESA-N 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N tryptophan Chemical compound C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/72—Two oxygen atoms, e.g. hydantoin
- C07D233/76—Two oxygen atoms, e.g. hydantoin with substituted hydrocarbon radicals attached to the third ring carbon atom
Definitions
- the present invention relates to hydantoins of the formula I,
- R is the residue of an amino carboxylic acid or of an amino carboxylic acid derivative which is obtained formally by removing an NH 2 group from an amino carboxylic acid or an amino carboxylic acid derivative, to the preparation thereof and to the use thereof as intermediates, in particular for preparing pharmaceutically active ingredients.
- a subject of the present invention therefore are the hydantoins of the formula I
- R is the residue of an amino carboxylic acid or of an amino carboxylic acid derivative which is obtained formally by removing an NH 2 group from an amino carboxylic acid or an amino carboxylic acid derivative, and the salts thereof.
- the compounds of the formula I thus contain in the residue R at least one carboxylic acid group COOH or a derivative thereof or a salt thereof.
- Amino carboxylic acid derivatives mean compounds which are obtained formally from the relevant amino carboxylic acid by converting one or more carboxylic acid groups into other groups which are directly related to the carboxylic acid group, for example ester groups, amide groups, nitrile groups, aldehyde groups or hydroxymethyl groups, in particular ester groups.
- ester groups are (CrCe)-alkyl esters such as methyl esters, ethyl esters, propyl esters such as n-propyl esters and isopropyl esters, butyl esters such as n-butyl esters, isobutyl esters, sec-butyl esters and tert-butyl esters, pentyl esters and hexyl esters, or phenyl-(CrC 4 )-alkyl esters such as benzyl esters.
- amide groups are unsubstituted amides (CONH 2 ), N-(C ⁇ -C 4 )-alkylamides and N,N-di-((C C 4 )-alkyl)amides such as N-methylamides and N,N-dimethylamides, N-methoxy-N-methylamides and N-benzylamides.
- the amino carboxylic acid or the amino carboxylic acid derivative of the formula H 2 N-R from which the residue R in the formula I is derived may be a natural or unnatural amino carboxylic acid or a derivative of a natural or unnatural amino carboxylic acid.
- the residue R or the amino carboxylic acid or the amino carboxylic acid derivative from which the residue R is derived may contain one or more other functional groups. All functional groups and carboxylic acid groups and derivatives of carboxylic acid groups may be present in protected form.
- Suitable protective groups such as, for example, urethane protective groups, carboxylic acid protective groups and side-chain protective groups are described in Hubbuch, Victore (Merck) 1979, No. 3, pages 14 to 23, and in B ⁇ llesbach, Gree (Merck) 1980, No. 1 , pages 23 to 35.
- Examples of functional groups which may be present in the residue R besides derivatives of carboxylic acid groups are hydroxyl, (CrC 4 )-alkoxy, ((C 1 -C 4 )- alkyl)carbonyloxy, benzyloxy, oxo, amino, ((C ⁇ -C 4 )-alkyl)carbonylamino such as acetylamino or isobutyrylamino, ((CrC 4 )-alkoxy)carbonylamino such as tert- butoxycarbonylamino, benzyloxycarbonylamino, 9-fluorenyImethyloxycarbonylamino, mercapto, (CrC4)-alkylmercapto, amidino, guanidino, etc., and protected forms of these groups.
- Compounds of the formula I which contain one or more basic groups, for example amino groups, guanidino groups or basic nitrogen heterocycles, may be present in the form of acid addition salts including salts with inorganic acids such as, for example, hydrogen chloride, hydrogen bromide, sulfuric acid or phosphoric acid, and salts with organic carboxylic acids and sulfonic acids, such as, for example, acetic acid, trifluoroacetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, methanesulfonic acid or p-toluenesulfonic acid.
- inorganic acids such as, for example, hydrogen chloride, hydrogen bromide, sulfuric acid or phosphoric acid
- organic carboxylic acids and sulfonic acids such as, for example, acetic acid, trifluoroacetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, methanesulfonic acid or p
- Compounds of the formula I which contain acidic groups, for example one or more carboxylic acid groups may, for example, be present in the form of metal salts, for example alkali metal salts or alkaline earth metal salts, such as lithium salts, sodium salts, potassium salts, magnesium salts or calcium salts, or in the form of ammonium salts including, for example, salts with quaternary ammonium ions and acid addition salts with ammonia and organic amines such as, for example, ethylamine, triethylamine, ethanolamine, tris(2-hydroxyethyl)amine, ⁇ , ⁇ , ⁇ -tris(hydroxymethyl)methylamine or amino acids.
- metal salts for example alkali metal salts or alkaline earth metal salts, such as lithium salts, sodium salts, potassium salts, magnesium salts or calcium salts
- ammonium salts including, for example, salts with quaternary ammonium ions and acid addition salts with ammonia and organic amines
- Salts may be obtained from the compounds of the formula I by conventional methods known to a person skilled in the art, for example by combining with an organic or inorganic acid or base in a solvent or diluent, or by anion exchange or cation exchange from other salts.
- the present invention encompasses the compounds of the formula I in all their tautomeric forms.
- the invention further encompasses solvates of compounds of the formula I, for example hydrates and adducts with alcohols.
- the present invention encompasses the compounds of the formula I in all stereoisomeric forms, for example enantiomers and diastereomers, and mixtures of two or more stereoisomeric forms, for example mixtures of enantiomers and/or diastereomers, in all ratios. If the compounds of the formula I contain one or more asymmetric centers, these may have, independently of one another, the S configuration or R configuration.
- the invention thus relates to enantiomers in enantiomerically pure form, both as levorotatory and as dextrorotatory antipodes, in the form of racemates and in the form of mixtures of the two enantiomers in all ratios.
- the invention likewise relates to diastereomers in diastereomerically pure form and in the form of mixtures of two or more diastereomers in all ratios. If a cis/trans isomerism is possible in the compounds of the formula I, for example if a double bond or a substituted cycloalkyl residue is present, the invention relates both to the cis form and to the trans form, or the Z form and the E form, and mixtures of these forms in all ratios. These statements apply correspondingly to the amino carboxylic acids and the amino carboxylic acid derivatives of the formula H 2 N-R from which the residue R is derived and which may be present in all stereochemical forms, for example in the D form, the L form or the DL form.
- stereoisomers can be prepared by using stereochemically pure starting materials in the synthesis, by stereoselective synthesis or by separating a mixture by conventional methods, for example by chromatography or crystallization, in the case of enantiomers for example by chromatography on chiral phases.
- a derivatization may take place where appropriate before a separation of stereoisomers.
- the separation of a stereoisomer mixture may take place at the stage of compounds of the formula I or at the stage of a starting material or of an intermediate during the synthesis.
- the residue R in the formula I is preferably derived from an ⁇ -amino carboxylic acid or an ⁇ -amino carboxylic acid derivative or a salt thereof, from a ⁇ -amino carboxylic acid or a ⁇ -amino carboxylic acid derivative or a salt thereof, from a -annino carboxylic acid or a ⁇ -amino carboxylic acid derivative or a salt thereof, or from an aromatic amino carboxylic acid or an aromatic carboxylic acid derivative or a salt thereof.
- the residue R in the formula I is particularly preferably derived from an ⁇ -amino carboxylic acid or an ⁇ -amino carboxylic acid derivative or a salt thereof or from a ⁇ -amino carboxylic acid or a ⁇ -amino carboxylic acid derivative or a salt thereof.
- the residue R in the formula I is very particularly preferably derived from an ⁇ -amino carboxylic acid or an ⁇ -amino carboxylic acid derivative or a salt thereof.
- ⁇ -Amino carboxylic acids mean compounds which contain at least one amino group and at least one carboxylic acid group, of which one amino group and one carboxylic acid group are separated from one another by one carbon atom.
- ⁇ -Amino carboxylic acids mean compounds which contain at least one amino group and at least one carboxylic acid group, of which one amino group and one carboxylic acid group are separated from one another by a chain of two carbon atoms.
- -Amino carboxylic acids mean compounds which contain at least one amino group and at least one carboxylic acid group, of which one amino group and one carboxylic acid group are separated from one another by a chain of three carbon atoms.
- Aromatic amino carboxylic acids mean compounds which contain at least one amino group and at least one carboxylic acid group which are bonded to a carbocyclic or heterocyclic aromatic ring system.
- the present invention thus provides a compound of the formula la or a derivative or salt thereof, or a compound of the formula lb or a derivative or salt thereof, or a compound of the formula lc or a derivative or a salt thereof, or a compound of the formula Id or a derivative or a salt thereof, particularly preferably a compound of the formula la or a derivative or a salt thereof, or a compound of the formula lb or a derivative or a salt thereof, very particularly preferably a compound of the formula la or a derivative or a salt thereof.
- the residues C(R )(R 2 )COOH etc. bonded to a ring nitrogen atom which are present in the compounds of formulae la etc. are subgeneric embodiments of the residue R which is present in the compounds of the formula 1.
- R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are, independently of one another, hydrogen, (CrC 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, (C 3 -C 7 )-cycloalkyl, (C 3 -C 7 )-cycloalkyl-(C ⁇ -C 4 )-alkyl, (C 6 -C 12 )-aryl,
- the groups representing R 1 , R 2 , R 3 , R 4 , R 5 and R 6 may be unsubstituted or be substituted by one or more identical or different substituents.
- the divalent residue Ar in the compounds of the formula Id is a divalent residue of a monocyclic or polycyclic aromatic ring system, for example of a monocyclic, bicyclic or tricyclic aromatic ring system, with 5 to 15 ring members including 5, 6, 8, 9, 10, 11 , 12, 13, 14 and 15 ring members, which can contain 1 , 2, 3 or 4 identical or different ring heteroatoms from the series nitrogen, oxygen and sulfur.
- the groups representing Ar may be unsubstituted or be substituted by one or more identical or different substituents.
- Derivatives of the compounds of the formulae la, lb, lc and Id are, as explained above for the compounds of the formula I, compounds in which the carboxylic acid groups depicted in the formulae la, lb, lc and Id and/or other carboxylic acid groups present in the molecules are converted into other functional groups, for example ester groups, amide groups, nitrile groups, aldehyde groups or hydroxymethyl groups, in particular ester groups.
- Alkyl groups, alkenyl groups and alkynyl groups may be straight-chain or branched.
- alkenyl and alkynyl are vinyl, prop-2-enyl (allyl), prop-1-enyl, but-2-enyl, but-3-enyl, 3-methylbut-2-enyl, penta-2,4-dienyl, ethynyl, prop-2-ynyl (propargyl), prop-1-ynyl, but-2-ynyl and but-3-ynyl.
- Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
- Examples of cycloalkylalkyl residues are cyclopropylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl, 3-cyclopropylpropyl, 4-cyclopropylbutyl, cyclobutylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, 1-cyclopentylethyl, 2-cyclopentylethyl, 3-cyclopentylpropyl, cyclohexyl methyl, 1-cyclohexyIethyl, 2-cyclohexylethyl, 3-cyclohexylpropyl, cycloheptylmethyl, 2-cycloheptylethyl.
- aryl groups are phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl and 4-biphenylyl, in particular phenyl.
- Heteroaryl groups are preferably derived from monocyclic 5-membered or 6-membered aromatic ring systems or bicyclic 9-membered or 10-membered aromatic ring systems which contain 1 , 2 or 3 identical or different heteroatoms from the series nitrogen, oxygen and sulfur, in particular from monocyclic 5-membered or 6-membered aromatic ring systems.
- heteroaryl examples include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, 1 ,3-oxazolyl, 1 ,2-oxazolyl, 1 ,3-thiazolyl, 1 ,2-thiazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, indoiyl, benzofuranyl, benzothienyl, benzimidazolyl, 1 ,3-benzoxazolyl, 1 ,3-benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, etc.
- a heteroaryl residue may be bonded via any suitable position.
- a thienyl residue may be present in the form of the 2-thienyl residue or 3-thienyl residue
- a furyl residue may be present in the form of the 2-furyl residue or 3-furyl residue
- a pyridyl residue may be present in the form of the 2-pyridyl residue, 3-pyridyl residue or 4-pyridyl residue.
- a residue derived from 1 ,3-thiazole or from imidazole may be bonded via the 2 position, the 4 position or the 5 position, a residue derived from quinoline via the 2 position, 3 position, 4 position, 5 position, 6 position, 7 position, 8 position.
- arylalkyl residues are benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, (l-naphthyl)methyl, (2-naphthyl)methyl, 1-(1-naphthyl)ethyl, 1-(2-naphthyl)ethyl, 2-(1-naphthyl)ethyl, 2-(2-na ⁇ hthyl)ethyl, (2-biphenylyl)methyl, (3-biphenylyl)methyI, (4-biphenylyl)methyl.
- heteroarylalkyl residues are (2-pyridyl)methyl, (3-pyridyl)methyl, (4-pyridyl )methyl, 2-(2-pyridyl)ethyl, 2-(3-pyridyl)ethyl, 2-(4-pyridyl)ethyl, (2-thienyl)methyl, (3-thienyl)methyl, 2-(2-thienyl)ethyl, 2-(3-thienyl)ethyl, (4-imidazolyl)methyl, (3-indolyl)methyl.
- aryl groups and heteroaryl groups apply correspondingly to the divalent group Ar in the compounds of the formula Id which is derived from a carbocyclic or heterocyclic aromatic ring system.
- the residues Ar may, for example, be derived from the aromatic residues listed above.
- divalent residue Ar examples include phenylene, biphenylylene (biphenyldiyl), naphthylene (naphthalenediyl), fluorenylene (fluorenediyl), anthracenediyl, thiophenediyl, furandiyl, pyrrolediyl, pyrazolediyl, imidazolediyl, thiazolediyl, pyridinediyl, pyridazinediyi, pyrimidinediyl, pyrazinediyl, indolediyl, benzothiophenediyl, quinolinediyl, isoquinolinediyl, carbazolediyl, phenothiazinediyl.
- the residue Ar may be bonded via any suitable positions of the aromatic ring system.
- a phenylene residue may be a 1 ,2-, 1 ,3- or 1 ,4-phenylene residue
- a naphthalenediyl residue may be a 1,2-, 1,3-, 1 ,4-, 1 ,5-, 1 ,6-, 1 ,7-, 1 ,8-, 2,3-, 2,6- or 2,7-naphthalenediyl residue
- a thiophenediyl residue may be a 2,3-, 2,4-, 2,5- or 3,4-thiophenediyl residue
- a pyridinediyl residue may be a 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-pyridinediyl residue.
- alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl groups representing R 1 , R 2 , R 3 , R 4 , R 5 and R ⁇ may be unsubstituted or carry one or more, for example one, two, three or four, identical or different substituents, in the case of the cycloalkylalkyl, arylalkyl and heteroarylalkyl groups in particular in the cyclic moiety.
- carboxylic acid groups hydroxycarbonyl groups, carboxyl groups, COOH groups
- possible substituents which may be present in R , R 2 , R 3 , R 4 , R 5 and R 6 are, for example, halogen including fluorine and chlorine, trifluoromethyl, hydroxyl, (C ⁇ -C )-alkoxy, benzyloxy, oxo, nitro, amino, ((C ⁇ -C )-alkyl)carbonylamino, ((C ⁇ -C )-alkoxy)carbonylamino,
- Cycloalkyl groups, aryl groups and heteroaryl groups may also carry (C ⁇ -G )-alkyl residues, for example methyl residues, as substituents.
- the substituents in substituted residues may be present in any suitable positions as long as the resulting compound is stable and suitable for the desired purpose.
- the substituent in monosubstituted phenyl residues may be present in the 2 position, the 3 position or the 4 position.
- the substituents in disubstituted phenyl residues may be present in the 2,3 position, 2,4 position, 2,5 position, 2,6 position, 3,4 position or 3,5 position.
- the above explanations apply correspondingly to the substituents which may be present in the residue Ar.
- the R 2 group in the compounds of the formula la is preferably hydrogen or methyl.
- the R 2 and/or R 3 and/or R 4 groups are, independently of one another, hydrogen or methyl, or the R 1 and/or R 2 and/or R 4 groups are, independently of one another, hydrogen or methyl.
- the R 2 and/or R 3 and/or R 4 and/or R 5 and/or R 6 groups are, independently of one another, hydrogen or methyl, or the R 1 and/or R 2 and/or R 4 and/or R 5 and/or R 6 groups are, independently of one another, hydrogen or methyl, or the R 1 and/or R 2 and/or R 3 and/or R 4 and/or R 6 groups are, independently of one another, hydrogen or methyl.
- the Ar group in the compounds of the formula Id is preferably a divalent residue of a 5-membered or 6-membered monocyclic aromatic ring system or of a 9-membered or 10-membered bicyclic aromatic ring system which can contain 1 or 2 identical or different ring heteroatoms from the series nitrogen, oxygen and sulfur.
- the R 2 group in the compounds of the formula la is particularly preferably hydrogen.
- the R 2 , R 3 and R 4 groups are hydrogen or the R 1 , R 2 and R 4 groups are hydrogen.
- the compounds of the formula lc particularly preferably the R 2 , R 3 , R 4 , R 5 and R 6 groups are hydrogen or the R 1 , R 2 , R 4 , R 5 and R 6 groups are hydrogen or the R 1 , R 2 , R 3 , R 4 and R 6 groups are hydrogen.
- the Ar group in the compounds of the formula Id is particularly preferably a divalent residue of a 5-membered or 6-membered monocyclic aromatic ring system which can contain 1 or 2 identical or different ring heteroatoms from the series nitrogen, oxygen and sulfur, for example a phenylene residue or a thiophenediyl residue.
- a very particularly preferred embodiment of the present invention provides a compound of the formula le or a derivative or salt thereof.
- R 1 in the compounds of the formula le has the meanings indicated above and may be substituted as indicated above.
- Derivatives of compounds of the formula le mean, as explained above, compounds in which the carboxylic acid group depicted in the formula le, and/or other carboxylic acid groups present in the molecule, are converted into other functional groups, for example ester groups, amide groups, nitrile groups, aldehyde groups or hydroxymethyl groups, in particular ester groups.
- the residue -CHR 1 -COOH in the compounds of the formula le is derived formally from an ⁇ -amino carboxylic acid of the formula H 2 N-CHR 1 -COOH by removal of the H 2 N group. According to a usual way of viewing the R 1 residue in the compounds of the formula le and in the amino carboxylic acids of the formula H 2 N-CHR -COOH, R 1 corresponds to the side chain of the ⁇ -amino carboxylic acid.
- Examples of such side chains and of the R 1 residue in the formula le are alkyl residues, for example the methyl, isopropyl and isobutyl side chains present in alanine, valine or leucine, the cyclopropylmethyl side chain present in ⁇ -cyclopropylalanine, the benzyl side chain present in phenylalanine, the phenyl side chain present in phenylglycine, the 4-aminobutyl side chain present in lysine or the hydroxycarbonylmethyl side chain present in aspartic acid.
- functional groups in the side chain of the ⁇ -amino carboxylic acid from which the -CHR 1 -COOH residue in the compounds of the formula le may be derived may be present in protected form.
- R 1 in the compounds of the formulae la, lb, lc and le is preferably hydrogen, (Cr C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl or (C 3 -C )-cycloalkyl-(C ⁇ -C4)-alkyl, particularly preferably (C ⁇ -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, (C 3 -C 7 )-cycloalkyl-(C 1 -C 4 )-alkyl, very particularly preferably (C C 6 )-alkyl or (C 3 -C 6 )-cycloalkyl-(C ⁇ -C 2 )-alkyl, in particular (C 3 -C 5 )-alkyl or (C 3 -C 6 )-cycIoalkyl-(CrC 2 )-alkyl.
- R 1 in particular in the compounds of the formula le, are isopropyl ((CH 3 ) 2 CH-), isobutyl ((CH 3 ) 2 CH-CH 2 -), neopentyl ((CH 3 ) 3 C-CH 2 -), cyclopropylmethyl (cycloC 3 H 5 -CH 2 -), cyclobutylmethyl (cycloC 4 H 7 -CH 2 -) and cyclopentylmethyl (cycloC 5 H 9 -CH 2 -), specifically isobutyl and cyclopropylmethyl.
- the asymmetric carbon atom to which the R 1 group is bonded in compounds of the formula le preferably has the S configuration.
- R' residue in the formula III has the meanings stated above for the R residue in formula I, but free carboxylic acid groups are present in the compounds of the formula III in esterified form, for example in the form of the (C C 6 )-alkyl esters or benzyl esters, such as in the form of the tert-butyl esters, and other functional groups, for example aldehyde groups or hydroxymethyl groups, may be or must be present in protected form or in the form of precursors, as already explained above for compounds of the formula I.
- a subject of the present invention also is a process for preparing the compounds of the formula I, which comprises reacting the compound of the formula II with a compound of the formula III. In the compounds of the formula I obtained as direct products of the reaction of compounds of the formulae II and III it is subsequently possible to modify functional groups.
- ester groups can be converted by standard methods into carboxylic acid groups, for example by hydrolysis with an acid such as hydrochloric acid or, in the case of tert-butyl esters, by treating with trifluoroacetic acid. It is also possible for an ester group of a particular type, for example a tert-butyl ester, to be converted selectively into a carboxylic acid group, and an ester group of another type, for example an ethyl ester, to be left unchanged. A further example which may be mentioned is the liberation of protected aldehyde groups or hydroxymethyl groups.
- the reaction of compounds of the formulae II and III is advantageously carried out in an inert solvent such as a hydrocarbon or ether, for example benzene or toluene, generally at temperatures from about 20°C to about 80°C.
- an inert solvent such as a hydrocarbon or ether, for example benzene or toluene
- the reaction mixture is heated to a temperature of from about 40°C to about 80°C, for example to about 60°C.
- the volatile components can be removed in vacuo and the crude product of the formula I can be purified by standard methods, for example by chromatography.
- the 2-tert-butoxy-4,4-bis(trifluoromethyl)-1 ,3-oxazabuta-1 ,3-diene of the formula II can be obtained by the method described by Steglich et al., Chemische Berichte 107 (1974), 1488.
- the starting materials are tert-butyl carbamate ((CH 3 ) 3 C-O-CO-NH 2 ) and anhydrous hexafluoroacetone which are initially reacted, for example in a solvent such as dichloromethane at room temperature, to give 2-tert-butoxycarbonylamino- 2-hydroxy-1 ,1 ,1 ,3,3,3-hexafluoropropane.
- This intermediate is then converted, for example in a solvent such as diethyl ether at temperatures from about 0°C to about 10°C, by treatment with trifluoroacetic anhydride in the presence of a base such as quinoline into the compound of the formula II, which can be purified by distillation. Details of the preparation are described below.
- the isocyanides (isonitriles) of the formula III can be obtained by standard methods known to a person skilled in the art from the respective amino carboxylic acid derivatives of the formula H 2 N-R' in which R' has the meaning indicated for formula III.
- This N-formyl compound is then converted, for example by reaction with phosgene or a phosgene equivalent such as diphosgene or triphosgene, in the presence of a tertiary amine such as triethylamine in a solvent such as dichloromethane at temperatures from about -40°C to about 0°C into the isocyanide of the formula III.
- phosgene or a phosgene equivalent such as diphosgene or triphosgene
- the compounds of the formula I are valuable intermediates for preparing pharmaceutically active compounds which comprise a 2,5-dioxo-4,4- bis(trifluoromethyl)imidazolidine ring whose 1 position is bonded to a structural element which is obtained formally from an amino carboxylic acid or an amino carboxylic acid derivative by removal of an amino group, and whose 3 position may optionally carry an additional substituent.
- pharmaceutically active compounds are antagonists of the integrin VLA-4 as are described, for example, in EP-A-918059 or WO-A-99/60015 and can be represented by formula IV
- the divalent residue -D-CO- is the residue of an amino carboxylic acid or of an amino carboxylic acid derivative which is obtained formally by removal of an NH 2 group from an amino carboxylic acid and by removal of the hydroxyl group from the carboxylic acid group
- the residue -NH-E is the residue of an amino compound such as, for example, of an amino acid, of an amino acid ester, of a dipeptide or of an amino alcohol, which is obtained formally by removal of a hydrogen atom from an amino group
- R 10 is, for example, an optionally substituted arylalkyl residue, for example a substituted benzyl residue.
- Compounds of the formula I can be converted into a pharmaceutically active compound, for example, by first introducing a substituent on the nitrogen atom in the 3 position, for example by an alkylation with a halogen compound such as a substituted benzyl chloride or benzyl bromide in the presence of a base, and subsequently, where appropriate after removal of protective groups, reacting a functional group present in the R residue, for example a carboxylic acid group or a derivative thereof such as an ester group, amide group, nitrile group, aldehyde group or hydroxymethyl group, with a further synthon.
- a halogen compound such as a substituted benzyl chloride or benzyl bromide
- a compound of the formula IV is preferably synthesized by employing a compound of the formula I in which R contains a carboxylic acid group, and which is reacted under standard conditions in the presence of a condensing reagent as is known from peptide chemistry for generating amide bonds, for example TOTU or a carbodiimide such as N,N'- dicyclohexylcarbodiimide, with a compound of the formula H 2 N-E, for example an amino acid ester or an amino alcohol.
- Subjects of the present invention also are the use of the compounds of the formula I as intermediates, in particular for preparing pharmaceutically active ingredients, and a process for preparing pharmaceutically active ingredients which comprise a 2,5-dioxo-4,4-bis(trifluoromethyl)imidazolidine ring whose 1 position is bonded to a synthon which is obtained formally from an amino carboxylic acid or an amino carboxylic acid derivative by removal of an amino group, and whose 3 position may optionally carry an additional substituent, which process comprises reacting a functional group which is present or liberated in the residue R in the formula I, for example the carboxylic acid group or a derivative thereof which is present in the residue R, with a further synthon and optionally introducing an additional substituent in the 3 position.
- HFA hexafluoroacetone
- reaction solution was then washed at room temperature twice with 7% strength sodium hydrogencarbonate solution.
- the phases were separated and the organic phase was dried over magnesium sulfate. After filtration, the solvent was removed in vacuo, and the residue was taken up in 70 ml of benzene. 3 g
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE60221660T DE60221660T2 (en) | 2001-03-10 | 2002-02-23 | BIS (TRIFLUOROMETHYL) HYDANTOINE AS INTERMEDIATE PHARMACEUTICAL ACTIVE INGREDIENTS |
EP02724181A EP1381595B1 (en) | 2001-03-10 | 2002-02-23 | Bis(trifluoromethyl)hydantoins as intermediates for pharmaceutically active ingredients |
JP2002571473A JP4340065B2 (en) | 2001-03-10 | 2002-02-23 | Bis (trifluoromethyl) hydantoin as an intermediate for pharmaceutically active ingredients |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10111876.7 | 2001-03-10 | ||
DE10111876A DE10111876A1 (en) | 2001-03-10 | 2001-03-10 | Bis (trifluoromethyl) hydantoins as intermediates for active pharmaceutical ingredients |
Publications (1)
Publication Number | Publication Date |
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WO2002072557A1 true WO2002072557A1 (en) | 2002-09-19 |
Family
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2002/001918 WO2002072557A1 (en) | 2001-03-10 | 2002-02-23 | Bis(trifluoromethyl)hydantoins as intermediates for pharmaceutically active ingredients |
Country Status (6)
Country | Link |
---|---|
US (1) | US6794517B2 (en) |
EP (1) | EP1381595B1 (en) |
JP (1) | JP4340065B2 (en) |
AT (1) | ATE369345T1 (en) |
DE (2) | DE10111876A1 (en) |
WO (1) | WO2002072557A1 (en) |
Families Citing this family (2)
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CN112312910A (en) * | 2018-04-12 | 2021-02-02 | 莫菲克医疗股份有限公司 | Human integrin alpha 4 beta 7 antagonists |
CU20220027A7 (en) | 2019-10-16 | 2022-12-12 | Morphic Therapeutic Inc | CHEMICAL COMPOUNDS DERIVED SUBSTITUTED FROM PROPANOIC ACID USEFUL IN THE INHIBITION OF HUMAN INTEGRIN A4β7 AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996033976A1 (en) * | 1995-04-28 | 1996-10-31 | Hoechst Aktiengesellschaft | Hydantoine derivatives as intermediate products for active pharmaceutical agents |
EP0903353A1 (en) * | 1997-09-18 | 1999-03-24 | Hoechst Marion Roussel Deutschland GmbH | Imidazolidine derivates, their preparation and use, and pharmaceutical compositions containing them |
EP0905139A2 (en) * | 1997-09-23 | 1999-03-31 | Hoechst Marion Roussel Deutschland GmbH | 5 ring heterocyles, process for preparation, use as inhibitors of leukocyte adhesion and pharmaceutical preparations comprising them |
WO1999060015A1 (en) * | 1998-05-14 | 1999-11-25 | Aventis Pharma Deutschland Gmbh | Imidazolidine derivatives, the production thereof, their use and pharmaceutical preparations containing the same |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE19751251A1 (en) | 1997-11-19 | 1999-05-20 | Hoechst Marion Roussel De Gmbh | Substituted imidazolidine derivatives, their manufacture, their use and pharmaceutical preparations containing them |
-
2001
- 2001-03-10 DE DE10111876A patent/DE10111876A1/en not_active Withdrawn
-
2002
- 2002-02-23 WO PCT/EP2002/001918 patent/WO2002072557A1/en active IP Right Grant
- 2002-02-23 EP EP02724181A patent/EP1381595B1/en not_active Expired - Lifetime
- 2002-02-23 AT AT02724181T patent/ATE369345T1/en not_active IP Right Cessation
- 2002-02-23 DE DE60221660T patent/DE60221660T2/en not_active Expired - Lifetime
- 2002-02-23 JP JP2002571473A patent/JP4340065B2/en not_active Expired - Fee Related
- 2002-03-08 US US10/092,889 patent/US6794517B2/en not_active Expired - Lifetime
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996033976A1 (en) * | 1995-04-28 | 1996-10-31 | Hoechst Aktiengesellschaft | Hydantoine derivatives as intermediate products for active pharmaceutical agents |
EP0903353A1 (en) * | 1997-09-18 | 1999-03-24 | Hoechst Marion Roussel Deutschland GmbH | Imidazolidine derivates, their preparation and use, and pharmaceutical compositions containing them |
EP0905139A2 (en) * | 1997-09-23 | 1999-03-31 | Hoechst Marion Roussel Deutschland GmbH | 5 ring heterocyles, process for preparation, use as inhibitors of leukocyte adhesion and pharmaceutical preparations comprising them |
WO1999060015A1 (en) * | 1998-05-14 | 1999-11-25 | Aventis Pharma Deutschland Gmbh | Imidazolidine derivatives, the production thereof, their use and pharmaceutical preparations containing the same |
Also Published As
Publication number | Publication date |
---|---|
JP4340065B2 (en) | 2009-10-07 |
EP1381595A1 (en) | 2004-01-21 |
DE60221660T2 (en) | 2008-06-19 |
JP2004519491A (en) | 2004-07-02 |
US20020183374A1 (en) | 2002-12-05 |
US6794517B2 (en) | 2004-09-21 |
DE10111876A1 (en) | 2002-09-19 |
DE60221660D1 (en) | 2007-09-20 |
EP1381595B1 (en) | 2007-08-08 |
ATE369345T1 (en) | 2007-08-15 |
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